PHYLOGENOMIC, TRANSCRIPTOMIC, VIROMIC, AND IMMUNOPROTEOMIC DETERMINANTS OF NECROTIZING ENTEROCOLITIS

坏死性小肠结肠炎的系统基因组、转录组、病毒组和免疫蛋白质组决定因素

• 批准号: 10164835
• 负责人: Gautam Dantas
• 金额: $ 58.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164835
• 关键词: Anaerobic Bacteria; Appearance; Archives; Bacteria; Bacteriophages; Biological; Biological Markers; Biology; Birth; Case Fatality Rates; Child; Cities; Clinical; Collection; Complication; Consent; Consequentialism; Data; Development; Enrollment; Event; Feces; Functional disorder; Gammaproteobacteria; Genetic Transcription; Genomics; Genotype; Gestational Age; Goals; Human; Immune response; Individual; Infant; Inflammation; Injury; Intervention; Intestines; Knowledge; Lead; Learning; Life; Link; Low Birth Weight Infant; Metadata; Microbe; Modeling; Molds; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal Intensive Care Units; Oklahoma; Organism; Outcome; Personal Satisfaction; Phylogenetic Analysis; Plasma; Play; Population; Premature Birth; Premature Infant; Prevention strategy; Process; Prospective cohort study; Publications; Publishing; Reaction; Resources; Risk; Role; Sampling; Series; Serum; Severities; Site; Specimen; System; Testing; Time; Transcriptional Activation; Very Low Birth Weight Infant; Virus; Work; bacterial community; base; case control; cohort; congenital heart disorder; dysbiosis; experience; gut bacteria; insight; intestinal injury; metabolomics; microbial; microbial host; microbiome; microbiota; mortality; novel; organ injury; prevent; stool sample; transcriptomics

Project Summary Necrotizing enterocolitis in very low birth weight infants remains a major challenge. Our reactive clinical approach to necrotizing enterocolitis has changed little in four decades. Morbidity and mortality from necrotizing enterocolitis remain unacceptably high, and preventive strategies rely on interventions with limited, if any, efficacy. We have assembled an extensive set of specimens, accompanied by rich clinical metadata, with which to define mechanisms that underlie the development of necrotizing enterocolitis in very preterm infants. Our proposal extends our recently published findings that a gut bacterial dysbiosis, characterized by over-representation of Gammaproteobacteria and under-representation of obligate anaerobic bacteria, precede, and plausibly contribute to, the development of necrotizing enterocolitis. Our overarching hypothesis is that identifiable microbial and/or host mechanisms signify an infant at risk for necrotizing enterocolitis. Our long-term goals are to use our knowledge of microbial-driven pathophysiology in necrotizing enterocolitis to build interventions to prevent the assembly of dysbiotic gut bacterial populations, to characterize the host biology prior to the sudden appearance of necrotizing enterocolitis. By generating these data, we hope to lessen the severity of necrotizing enterocolitis, or to prevent it altogether. Our Specific Aims are: (1) Conduct a comprehensive genomic analysis of gut bacteria prior to necrotizing enterocolitis onset, and (2) Define the gut biology and host response prior to necrotizing enterocolitis onset. All specimens from cases will be those obtained before this event occurred. Control materials will be matched to cases, according to gestational age at birth, and day of life specimens were produced. To accomplish these Aims, we will use our archive of pre-event stools and sera/plasmas from 977 very low birthweight infants from three neonatal intensive care units. Forty-six of these infants experienced NEC, after excluding those who also had congenital heart disease. We will employ genomic characterization of isolates, transcriptomics, metabolomics, viromics, and immunoproteomics in coordinated analyses to illuminate microbial and host biology underlying necrotizing enterocolitis. We will also interrogate populations of bacteria associated with protection from necrotizing enterocolitis. All studies will initially analyze a primary cohort from St. Louis, and then validate findings in specimens from Oklahoma City and Louisville. These case-control and time-series comparisons will provide mechanistic insight into an intractable and highly consequential complication of preterm birth, using an exceptionally relevant system, i.e., the colonized human infant. By project conclusion, we will generate mechanistically-informed data to guide attempts to better anticipate, treat, or, ideally, prevent, necrotizing enterocolitis, a devastating complication of preterm birth.

项目摘要 在非常低的出生体重婴儿中坏死性小肠结肠炎仍然是一个主要挑战。我们的反应性临床 在四十年中，坏死性小肠结肠炎的方法几乎没有改变。发病率和死亡率 坏死性小肠结肠炎的高度仍然高，预防策略依赖于有限的干预措施， 如果有的话，功效。我们组装了一套广泛的标本，并伴随着丰富的临床元数据 用来定义在非常早产中坏死性小肠结肠炎发展基础的机制 婴儿。我们的提议扩展了我们最近发表的发现，肠道细菌性营养不良，其特征是 γ虫细菌的过分占主张和厌氧细菌的占代表性不足， 在坏死性小肠结肠炎的发展之前，并有效。 我们的总体假设是，可识别的微生物和/或宿主机制表示婴儿 坏死性小肠结肠炎的风险。我们的长期目标是利用我们对微生物驱动的知识 坏死性小肠结肠炎的病理生理，以建立干预措施，以防止组装失调肠 细菌种群，以突然出现坏死之前表征宿主生物学 小肠结肠炎。通过生成这些数据，我们希望减轻坏死性小肠结肠炎的严重程度，或防止 它完全。 我们的具体目的是：（1）对肠道细菌进行全面的基因组分析 坏死性小肠结肠炎，（2）在坏死之前定义肠道生物学和宿主反应 小肠结肠炎发作。所有案件的标本都是在此事件发生之前获得的标本。控制 根据出生时的胎龄，材料将与案例相匹配，生命标本的日期为 生产。 为了实现这些目标，我们将使用977年的事件前粪便和血清/等离子体的档案 来自三个新生儿重症监护病房的低出生体重婴儿。这些婴儿中有46个经历了NEC， 在排除那些也患有先天性心脏病的人之后。我们将采用基因组表征 在协调的分析中，分离株，转录组学，代谢组学，病毒组学和免疫蛋白质组学以阐明 微生物和宿主生物学基础坏死性小肠结肠炎。我们还将询问细菌种群 与防止坏死性小肠结肠炎有关。所有研究最初将从 圣路易斯，然后在俄克拉荷马城和路易斯维尔的标本中验证发现结果。这些案例对照和 时间序列比较将为棘手且高度结果提供机械洞察力 早产的并发症，使用异常相关的系统，即殖民的人类婴儿。 通过项目结论，我们将生成机械知识的数据，以指导尝试改善的尝试 预测，治疗或理想情况下，预防，坏死性小肠结肠炎，是早产的毁灭性并发症。

项目成果

Approaches for characterizing and tracking hospital-associated multidrug-resistant bacteria.

• DOI: 10.1007/s00018-020-03717-2
• 发表时间: 2021-03
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Blake KS;Choi J;Dantas G
• 通讯作者: Dantas G

The effect of legume supplementation on the gut microbiota in rural Malawian infants aged 6 to 12 months.

• DOI: 10.1093/ajcn/nqaa011
• 发表时间: 2020-02
• 期刊: The American journal of clinical nutrition
• 作者: M. I. Ordiz;Stefan Janssen;G. Humphrey;G. Ackermann;Kevin B. Stephenson;Sophia E. Agapova;O. Divala;Yankho Kaimila;K. Maleta;Caroline Zhong;R. Knight;Indi Trehan;P. Tarr;B. Rusconi;M. Manary

Cotrimoxazole Prophylaxis Increases Resistance Gene Prevalence and α-Diversity but Decreases β-Diversity in the Gut Microbiome of Human Immunodeficiency Virus-Exposed, Uninfected Infants.

• DOI: 10.1093/cid/ciz1186
• 发表时间: 2020-12-31
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: D'Souza AW;Moodley-Govender E;Berla B;Kelkar T;Wang B;Sun X;Daniels B;Coutsoudis A;Trehan I;Dantas G
• 通讯作者: Dantas G

Draft Genome Sequence of a Mycobacterium Strain Isolated from a Clinical Wound Sample.

• DOI: 10.1128/mra.00170-22
• 发表时间: 2022-07-21
• 期刊: Microbiology resource announcements
• 影响因子: 0.8

Effect of amoxicillin on the gut microbiome of children with severe acute malnutrition in Madarounfa, Niger: a retrospective metagenomic analysis of a placebo-controlled trial.

• DOI: 10.1016/s2666-5247(23)00213-6
• 发表时间: 2023-11
• 期刊: LANCET MICROBE
• 影响因子: 38.2
• 作者: Schwartz, Drew J.;Langdon, Amy;Sun, Xiaoqing;Langendorf, Celine;Berthe, Fatou;Grais, Rebecca F.;Trehan, Indi;Isanaka, Sheila;Dantas, Gautam
• 通讯作者: Dantas, Gautam